Bedaquiline Resistance and Molecular Characterization of Rifampicin-Resistant Mycobacterium Tuberculosis Isolates in Zhejiang, China

Purpose: This study aimed to determine the prevalence and molecular characterization of bedaquiline (BDQ) resistance among rifampicin-resistant tuberculosis (RR-TB) isolates collected from Zhejiang, China.Patients and Methods: A total of 245 RR-TB isolates were collected from 19 municipal TB hospitals in Zhejiang province, China between January and December 2021. Microplate assays were used to determine the minimum inhibitory concentrations (MIC) of BDQ. Whole-genome sequencing (WGS) was performed on isolates with MIC values for BDQ >= 0.25 mu g/mL.Results: Five (2.04%) BDQ-resistant strains were isolated from 245 tuberculosis patients. The resistance rate of BDQ was not correlated to the sex, age, treatment history, or occupation of patients. Four BDQ-resistant isolates and three BDQ-sensitive isolates were found to carry Rv0678 mutations, and one BDQ-resistant strain carried both Rv0678 and pepQ mutations. No mutations within the atpE and Rv1979c genes were observed. Conclusion: BDQ demonstrated strong in vitro antibacterial activity against RR-TB isolates, and the Rv0678 gene was identified as the primary mechanism contributing to BDQ resistance among RR-TB isolates from Zhejiang, China. Furthermore, in addition to the four currently known resistance-associated genes (atpE, Rv0678, Rv1979c , and pepQ), other mechanisms of resistance to BDQ may exist that need further study. Plain language summary: This study looked at a bacterial species called Mycobacterium tuberculosis, which causes the highly problematic disease, tuberculosis. Certain strains of this bacterium have developed resistance to conventional antibiotics used in tuberculosis treatment, necessitating an investigation into the efficacy of the newer antibiotic, bedaquiline. We collected 245 rifampicin-resistant tuberculosis samples from patients in Zhejiang, China, subjecting them to bedaquiline susceptibility testing. Concurrently, we conducted a genetic analysis of the bacteria to pinpoint mutations linked to bedaquiline resistance. Out of the 245 samples, 5 were found to be resistant to bedaquiline. We found that mutations in a gene called Rv0678 were the main reason for this resistance. This gene had mutations in four of the bedaquiline-resistant samples and three of the bedaquiline-susceptible samples. One of the bedaquiline-resistant samples had mutations in both Rv0678 and another gene called pepQ. We also found that bedaquiline was effective at killing drug-resistant tuberculosis bacteria in the lab. However, there may be other genes or mechanisms that make other bacteria resistant to the drug, which will need further study. Overall, this study helps us understand how bedaquiline works against drug-resistant tuberculosis bacteria and identifies a genetic mechanism that can cause resistance to the drug.

Automated summary

This study aimed to determine the prevalence and molecular characterization of bedaquiline resistance among rifampicin-resistant tuberculosis isolates in Zhejiang, China. The results showed that bedaquiline exhibited strong antibacterial activity against rifampicin-resistant tuberculosis isolates, and the Rv0678 gene was identified as the primary mechanism contributing to bedaquiline resistance in Zhejiang, China.